The present invention relates to compounds that inhibit 5-hydroxytryptamine reuptake and the use of those compounds on diseases mediated by 5HT receptors. Compounds that provide such inhibition can be useful, for example, as therapeutic anti-depressants.
Serotonin (5-hydroxytryptamine) neurotransmission is regulated and terminated by active transport via the serotonin transporter (SERT). The SERT is member of a large superfamily of sodium/chloride dependent transporters that carry biogenic amines and other biologically active substrates to the interior of cells (Amara S G, Kuhar M J. 1993. 16:73-93; Blakely R D, et al., 1994. J Exp Biol 196:263-281). Structurally related to dopamine and norepinephrine transporters (Nelson N. 1998. J Neurochem 71:1785-1803), the SERT is the primary site of action of diverse antidepressant drugs, ranging from tricyclics such as imipramine and amitriptyline, to serotonin selective reuptake inhibitors (SSRI""s) such as citalopram, fluoxetine and sertraline.
Antidepressant drugs delay the removal of extracellular serotonin from the synapse by blocking serotonin transport, thereby prolonging the duration of serotonin receptor activity. The increased availability of serotonin triggers a cascade of neuroadaptive processes, which produces symptom relief after two to four weeks. Presently known antidepressants also produce certain side effects and may selectively alleviate specific symptoms of depression (Nestler E J. 1998. Biol Psychiatry 44:526-533). Thus, it is desirable to develop novel antidepressants. The majority of clinically approved drugs to treat depression or obsessive-compulsive disorder are high affinity inhibitors of serotonin and/or norepinephrine transport. Of these transporter inhibitors, none are tropane analogs, they display low affinity for the dopamine transporter (DAT), and all contain an amine nitrogen in their structure.
Over the past decade, a wide array of tropane analogs with high affinity for the monoamine transporters have been synthesized in a program to develop cocaine medications (Madras B K, et al., 1990. Pharmacol Biochem Behav 35:949-953; Madras B K, et al., 1996. Synapse 24:340-348; Carroll F I, et al., 1992. J Med Chem 35:2497-2500; Meltzer P C, et al., 1994. J Med Chem 37:2001-2010; Kozikowski A P, et al., 1995. J Med Chem 38:3086-3093; Lomenzo S A, et al., 1997. J Med Chem 40:4406-4414; Davies H M, et al., 1994. J Med Chem 37:1262-1268). The majority of these compounds target the dopamine transporter and have not been considered candidate medications for depression because of stimulant or abuse liability concerns (Reith M E, et al., 1986. Biochem Pharmacol 35:1123-1129; Ritz M C, et al., 1987. Science 237:1219-1223; Madras B K, et al., 1989. J Pharmacol Exp Ther 251:131-141; Bergman J, et al., 1989. J Pharmacol Exp Ther 251:150-155). Tropane analogs selective for the serotonin over the dopamine transporter have been reported. (Blough B E, et al., 1996. J Med Chem 39:4027-4035; Blough B E, et al., 1997. J Med Chem 40:3861-3864; Smith M P, et al., 1998. J Am Chem Soc 1201:9072-9075; Davies, H M, et al., 1996. J Med Chem 39:2554-2558.
Psychotherapeutics drugs, including antidepressants, all incorporate an amine nitrogen into the structure. In fact, antidepressants presently used have an aromatic ring(s) and an amine nitrogen. Although the aromatic ring is an indispensable component of most drugs acting on biogenic amine receptors or transporters, we previously demonstrated that an amine nitrogen is not necessary for compounds to bind to or block the dopamine transporter (Madras B K, et al., 1996. Synapse 24:340-348; Meltzer P C, et al., 1997. J Med Chem 40:2661-2673; Meltzer P C, et al., 1999. Bioorg Med Chem Lett 9:857-862; Meltzer P C, 2000. J Med Chem 43:2982-2991). Biological activity of these compounds was retained if the amine nitrogen was replaced either by an oxygen (oxa) atom or a carbon (carba) atom (Madras B K, et al., 1996. Synapse 24:340-348; Madras B K, et al., 1998. Soc for Neurosci Abst 24:113.11, 278p; Madras B K, et al., Addiction Biology 5:351-359, 2000; Meltzer P C, 2000. J Med Chem 43:2982-2991).
It would be desirable to have high affinity non-amines with selectivity for the serotonin transporter and compounds that inhibit the transport of serotonin.
The present invention relates to the discovery that tropane compounds lacking an amine group show surprisingly effective results in treating certain neuropsychiatric disorders related to serotonin transport.
Compounds that are useful as therapeutic agents in the methods of the present invention include non-amine tropane compounds represented by the following general structural formula: 
wherein:
R1=COOCH3, COR3, lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or COR6;
R2=is a 6xcex1, 6xcex2, 7xcex1 or 7xcex2 substituent, which can be selected from H, OH, OR3, F, Cl, Br, and NHR3;
X=CH2, CHY, CYY1, CO, O, S; SO, SO2, or Cxe2x95x90CX1Y with the C, O or S atom being a member of the ring;
X1=NR3, CH2, CHY, CYY1 CO, O, S; SO, SO2, or NSO2R3;
R3=H, (CH2)nC6H4Y, C6H4Y, CHCH2, lower alkyl, lower alkenyl or lower alkynyl;
Y and Y1=H, Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)nCH3, COCH3, or C(CH3)3;
R4=CH3, CH2CH3, or CH3SO2;
R6=morpholinyl or piperidinyl;
Ar=phenyl-R5, naphthyl-R5, anthracenyl-R5, phenanthrenyl-R5, or diphenylmethoxy-R5;
R5=Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)nCH3, COCH3, C(CH3)3 where n=0-6, 4-F, 4-Cl, 4-I, 2-F, 2-Cl 2-I, 3-F, 3-Cl 3-I, 3,4-diCl, 3,4-diOH, 3,4-diOAc, 3,4-diOCH3, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
m=0 or 1; and
n=0, 1, 2, 3, 4 or 5.
Preferred compounds have a SERT/DAT selectivity ratio of at least about 3. Other embodiments have a SERT/DAT selectivity ratio of at least about 8 and other preferably at least about 50.
The invention also relates to compounds shown above that have a potency (Ki), or IC50, at the SERT of less than about 500 nM, preferably less than about 100 nM. In certain preferred embodiments the compounds have a Ki at the SERT less than about 50 nM, preferably less than about 25 nM and more preferably less than about 15 nM.
Especially preferred compounds have a SERT/DAT selectivity ratio of at least about 3 and an IC50 at the SERT of less than about 500 nM.
The substituents at the 2 and 3 position of the ring can be xcex1- or xcex2-. Thus, the compounds include compounds in the boat and chair conformation. Although R1 is illustrated in the 2-position, it should be recognized that substitution at the 4-position is also included and the position is dependent on the numbering of the tropane ring. The compounds of the present invention can be racemic, pure R-enantiomers, or pure S-enantiomers. Thus, the structural formulas illustrated herein are intended to represent each enantiomer and diastereomer of the illustrated compound.
The term xe2x80x9clower alkylxe2x80x9d when used herein designates aliphatic saturated branched or straight chain hydrocarbon monovalent substituents containing from 1 to about 8 carbon atoms such as methyl, ethyl, isopropyl, n-propyl, n-butyl, (CH2)nCH3, C(CH3)3; etc., more preferably 1 to 4 carbons. The term xe2x80x9clower alkoxyxe2x80x9d designates lower alkoxy substituents containing from 1 to about 8 carbon atoms such as methoxy, ethoxy, isopropoxy, etc., more preferably 1 to 4 carbon atoms.
The term xe2x80x9clower alkenylxe2x80x9d when used herein designates aliphatic unsaturated branched or straight chain vinyl hydrocarbon substituents containing from 2 to about 8 carbon atoms such as allyl, etc., more preferably 2 to 4 carbons. The term xe2x80x9clower alkynylxe2x80x9d designates lower alkynyl substituents containing from 2 to about 8 carbon atoms, more preferably 2 to 4 carbon atoms such as, for example, propyne, butyne, etc.
The terms substituted lower alkyl, substituted lower alkoxy, substituted lower alkenyl and substituted lower alkynyl, when used herein, include corresponding alkyl, alkoxy, alkenyl or alkynyl groups substituted with halide, hydroxy, carboxylic acid, or carboxamide groups, etc. such as, for example, xe2x80x94CH2OH, xe2x80x94CH2CH2COOH, xe2x80x94CH2CONH2, xe2x80x94OCH2CH2OH, xe2x80x94OCH2COOH, xe2x80x94OCH2CH2CONH2, etc. As used herein, the terms lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl are meant to include where practical substituted such groups as described above.
When X contains a carbon atom as the ring member, reference to X is sometimes made herein as a carbon group. Thus, when X is a carbon group, as that phrase is used herein, it means that a carbon atom is a ring member at the X position (i.e., the 8-position).
The present invention also relates to therapeutic uses of non-amine tropane analogs. More specifically, the invention relates to methods of treating patients having SERT related disorders, comprising administering to the patient a serotonin reuptake inhibiting amount of a non-amine compound. Such diseases include, but are not limited to, e.g., depression, anxiety, eating disorders and obsessive compulsive disorders and other. The methods specifically include therapies for treating depression.
More specifically, the invention relates to the use of non-amine topane compounds, as described further below, for the treatment of these diseases. Particularly preferred compounds comprise the compounds shown in FIG. 1 and described herein.
The present invention provides pharmaceutical therapeutic compositions comprising the compounds formulated in a pharmaceutically acceptable carrier for use in the present methods.
Further, the invention provides a method for inhibiting 5-hydroxytryptamine (Serotonin) reuptake of a monoamine transporter by contacting the monoamine transporter with a 5-hydroxy-tryptamine reuptake inhibiting (5-HT inhibiting) amount of a non-amine tropane compound. Inhibition of 5-hydroxy-tryptamine reuptake of a serotonin transporter in a mammal is provided in accord with the present invention by administering to the mammal a 5-HT inhibiting amount of a non-amine tropane compound in a pharmaceutically acceptable carrier.